Objective: To explore the molecular defects of insulin signalling in polycystic ovary and in vitro effects of troglitazone, one of the insulin sensitizers-thiazolidinediones on polycystic ovary syndrome (PCOS).
Method: The metabolic and mitogenic effects of insulin and insulin-like growth factor 1 (IGF-1) were examined in cultured human ovarian luteinizing granulosa cells from PCOS (n = 11) and normally ovulatory (as control, n = 33) women with vehicle or troglitazone (1 microg/ml).
Results: Basal rates were similar, but there were significant decreases in insulin-stimulated glucose incorporation into glycogen in PCOS cells, a metabolic action of insulin. However, IGF-1 response was found to be about twice greater in PCOS cells at all experimental concentrations with respect to thymidine incorporation compared to control cells, a mitogenic action. Troglitazone increased 2-3 fold the insulin-induced glycogen synthesis, but reduced the IGF-1 augmented responses of DNA synthesis in PCOS cells to within the range of control granulosa cells. As compared with control, PCOS granulosa cells had higher insulin receptor substrate 1 (IRS -1) expression, but lower IRS-2 expression. IRS-2 protein levels were increased and IRS-1 levels were reduced by troglitazone treatment, with a greater extent in the former.
Conclusions: There is a selective defect in insulin actions in PCOS granulosa cells, suggesting ovarian insulin resistance and this metabolic phenotype is associated with an enhanced IGF-1 mitogenic potential. Troglitazone could divergently alter signal protein expressions and thus insulin actions, as an ovarian insulin sensitizer and mitogen/steroidogenic inhibitor in PCOS.